CD38 is a type II transmembrane glycoprotein which is normally found on hemopoietic cells and in solid tissues. With regard to hemopoietic cells, the majority of medullary thymocytes are CD38+, resting and circulating T- and B-cells are CD38− and activated cells are CD38+. CD38 is also expressed on approximately 80% of resting NK cells and monocytes and on lymph node germinal center lymphoblasts, plasma B cells and some intrafollicular cells. CD38 can also be expressed by dendritic cells. A significant proportion of normal bone marrow cells, particular precursor cells, express CD38. In addition, 50-80% of umbilical cord blood cells is CD38+ and remains so in human blood for the first two to three years of life. In addition to lymphoid precursor cells, CD38 is also expressed on erythrocytes and on platelets. With regard to solid tissues, CD38 is expressed in the gut by intra-epithelial cells and lamina propria lymphocytes, by Purkinje cells and neurofibrillary tangles in the brain, by epithelial cells in the prostate, β-cells in the pancreas, osteoclasts in the bone, retinal cells in the eye, and sarcolemma of smooth and striated muscle.
CD38 is also expressed in a variety of malignant hematological diseases, including multiple myeloma, B-cell chronic lymphocytic leukemia, B-cell acute lymphocytic leukemia, Waldenström macroglobulinemia, primary systemic amyloidosis, mantle-cell lymphoma, pro-lymphocytic/myelocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, follicular lymphoma, NK-cell leukemia and plasma-cell leukemia. Expression of CD38 has been described on epithelial/endothelial cells of different origin, including glandular epithelium in prostate, islet cells in pancreas, ductal epithelium in glands, including parotid gland, bronchial epithelial cells, cells in testis and ovary and tumor epithelium in colorectal adenocarcinoma. Other diseases, where CD38 expression could be involved, include, e.g. broncho-epithelial carcinomas of the lung, breast cancer (evolving from malignant proliferation of epithelial lining in ducts and lobules of the breast), pancreatic tumors, evolving from the b-cells (insulinomas), tumors evolving from epithelium in the gut (e.g. adenocarcinoma and squamous cell carcinoma), carcinoma in the prostate gland, seminomas in testis and ovarian cancers. In CNS, neuroblastomas express CD38.
Other disclosures also suggest the role of CD38 in autoimmunity such as Graves disease and thyroiditis (Antonelli A, et. al., Clin. Exp. Immunol. 126, 426-431, 2001), and type 1 and 2 Diabetes (Mallone R and Perin P C, Diabetes Metab Res Rev 2006; 22: 284-294) and inflammation of airway smooth muscle cells during asthma (Desphande et al. 2004 am J Respir Cell Mol Biol 31: 36-42)
CD38 is a multifunctional protein. Functions ascribed to CD38 include both receptor mediation in adhesion and signaling events and (ecto-) enzymatic activity. As an ectoenzyme, CD38 uses NAD+ as substrate for the formation of cyclic ADP-ribose (cADPR) and ADPR, but also of nicotinamide and nicotinic acid-adenine dinucleotide phosphate (NAADP). cADPR has been shown to act as second messenger for Ca2+ mobilization from the endoplasmatic reticulum. The CD38/cyclic ADP ribose system: 1) in lung, contributes to airway smooth muscle tone and responsiveness through its effects on agonist induced elevation of intra-cellular Ca2+ (Desphande et al. 2005 Am J physiol Lung cell Mol Physiol 288: L773-L788), 2) regulates migration of neutrophil chemotaxis to bacterial chemoattractants, migration of DC precursors from blood to peripheral sites and migration of mature DCs from sites of inflammation to lymph nodes (Partida-Sanchez et al. Nat Med 7: 1209-121, 2001; Morita et al. 2008 J Pharmacol Sci. 2008 March; 106 (3):492-504; Partida-Sanchez et al. Immunity 20: 279-291, 2004), 3) is involved in astrocyte calcium signaling which has implications for neuroinflammation and HIV-1-associated dementia (Banerjee S. et. al., J. Neurimmune Pharmacol., 3, 154-164 (2008)), 4) regulates FcγR-mediated phagocytosis in murine macrophages (Song E., et. al., Biochem. and Biophys. Res. Comm., 367, 156-161, (2008), 5) is linked to insulin secretion Okamoto, Molecular and Cellular Biochemistry, 193, 115-118, 1999 and 6) has a key role in neuropeptide release and regulating maternal and social behaviors (Jin D et al. Nature 446: 41-45, 2007). In addition to signaling via Ca2+, CD38 signaling occurs via cross-talk with antigen-receptor complexes on T and B cells or other types of receptor complexes, e.g. MHC molecules, and is in this way involved in several cellular responses, but also in switching and secretion of IgG1.
Several anti-CD38 antibodies are described in the literature, for instance in Lande R, et al., Cell Immunol. 220 (1), 30-8 (2002), Ausiello C M, et al., Tissue Antigens. 56 (6), 539-47 (2000), and Cotner T, et al., Int J Immunopharmacol. 3 (3), 255-68 (1981). Antibody binding to CD38 can have different effects on the functions of CD38. For instance, mouse anti-CD38 antibody IB4 has been shown to induce T cell activation as indicated by Ca2+ mobilization in Jurkat cells (Zubiaur M, et al., J. Immunol. 159 (1), 193-205 (1997), to induce significant proliferation of peripheral blood mononuclear cells (PBMCs), to induce release of significant IL-6 levels and to induce release of detectable IFN-γ levels (Lande, Zubiaur Morra, Ansiello supra). Hara-Yokoyama et al. Int Immunopharmacol 8, 59-70 (2008) described one anti-mouse CD38 antibody (CS/2) which inhibits the NAD+ glycohydrolase activity of CD38 and another anti-mouse CD38 antibody (clone 90) which stimulates the NAD+ glycohydrolase activity of an isolated extracellular domain of CD38, but has little effect on the NAD+ glycohydrolase activity of cell-surface CD38. As it can be seen from data presented below, the antibodies of the present invention provide activity on the surface of CD38 positive cells.
WO2006099875 (Genmab) describes several human anti-CD38 antibodies, including 003 and 005. Antibody 005 was shown to inhibit the production of cGDPR from NGD+ by CD38.
In view of the multiple functions of human CD38, there is a need for new therapeutic antibodies that more specifically modulate particular functions of CD38.